Chapter 18 Slides PDF

18 Amino Acid Oxidation and the Production of Urea © 2021 Macmillan Learning  Principle 1 (1 of 7) The many paths for amino acid catabolism have two broad parts, one involving the amino groups and the other involving the carbon skeletons. All of the pathways for amino aci...

18 Amino Acid Oxidation and the Production of Urea © 2021 Macmillan Learning  Principle 1 (1 of 7) The many paths for amino acid catabolism have two broad parts, one involving the amino groups and the other involving the carbon skeletons. All of the pathways for amino acid degradation include a key step, always involving a pyridoxal phosphate cofactor, in which the α-amino group is separated from the carbon skeleton and shunted into the pathways of amino group metabolism. The carbon skeletons are broken down to citric acid cycle intermediates.  Principle 2 (1 of 4) Four amino acids—alanine, glutamate, glutamine, and aspartate—play key roles in the transport and distribution of amino groups. All are present in relatively high concentrations in one or many mammalian tissues. All are readily converted to key citric acid cycle intermediates.  Principle 3 (1 of 5) Metabolic pathways are not distinct. The various pathways for amino acid catabolism are elaborately intertwined with other catabolic and anabolic pathways.  Principle 4 (1 of 3) Free ammonia is toxic. Excess amino groups must be safely excreted. In mammals, the urea cycle serves this purpose.  Principle 5 (1 of 6) Each amino acid has a different catabolic fate. The varied carbon skeletons of amino acids are broken down via equally varied pathways. All can be oxidized to generate ATP. All but leucine and lysine can contribute to gluconeogenesis when needed. Overview of Amino Acid Catabolism in Mammals Metabolic Circumstances of Amino Acid Oxidation amino acids undergo oxidative degradation when: – amino acids released during protein turnover are not needed for new protein synthesis – ingested amino acids exceed the body’s needs for protein synthesis – cellular proteins are used as fuel because carbohydrates are either unavailable or not properly utilized 18.1 Metabolic Fates of Amino Groups  Principle 4 (2 of 3) Free ammonia is toxic. Excess amino groups must be safely excreted. In mammals, the urea cycle serves this purpose.  Amino Group Catabolism unless reused, amino groups are channeled into a single excretory end product  Ammonotelic, Ureotelic, and Uricotelic Animals ammonotelic animals = excrete amino nitrogen as ammonia – most aquatic species ureotelic animals = excrete amino nitrogen as urea – most terrestrial animals uricotelic animals = excrete amino nitrogen as uric acid – birds and reptiles  Clicker Question 1 Humans are: A. ammonotelic. B. ureotelic. C. uricotelic. D. All of the answers are correct. E. None of the answers are correct.  Clicker Question 1, Response Humans are: B. ureotelic. Most terrestrial animals are ureotelic, excreting amino nitrogen in the form of urea. Birds and reptiles are uricotelic, excreting amino nitrogen as uric acid. Most aquatic species, such as the bony fishes, are ammonotelic, excreting amino nitrogen as ammonia.  Principle 2 (2 of 4) Four amino acids—alanine, glutamate, glutamine, and aspartate—play key roles in the transport and distribution of amino groups. All are present in relatively high concentrations in one or many mammalian tissues. All are readily converted to key citric acid cycle intermediates.  Amino Acids Involved in Nitrogen Metabolism glutamate, glutamine, alanine, and aspartate are most easily converted into citric acid cycle intermediates: – glutamate to α-ketoglutarate – glutamine to α-ketoglutarate – alanine to pyruvate – aspartate to oxaloacetate  Dietary Protein Is Enzymatically Degraded to Amino Acids degradation occurs in the gastrointestinal tract gastrin = hormone secreted when dietary protein enters the stomach – stimulates the secretion of HCl and pepsinogen pepsinogen = zymogen that is converted to active pepsin by autocatalytic cleavage at low pH  Pepsin and Secretin pepsin = cleaves long polypeptide chains into a mixture of smaller peptides secretin = hormone secreted into the blood in response to low pH in the small intestine – stimulates the pancreas to secrete bicarbonate into the small intestine  Zymogens Are Secreted by the Exocrine Cells of the Pancreas cholecystokinin = hormone secreted into the blood in response to the arrival of peptides in the duodenum – stimulates secretion of several pancreatic proteases: trypsinogen is the zymogen of trypsin chymotrypsinogen is the zymogen of chymotrypsin procarboxypeptidases A and B are the zymogens of carboxypeptidases A and B  Trypsin and Pancreatic Trypsin Inhibitor enteropeptidase = a proteolytic enzyme that converts trypsinogen to trypsin trypsin = activates additional trypsinogen, chymotrypsinogen, the procarboxypeptidases, and proelastase pancreatic trypsin inhibitor = protein inhibitor that further protects the pancreas against self-digestion  Clicker Question 2 Cholecystokinin stimulates the secretion of which pancreatic enzymes? A. trypsinogen B. chymotrypsinogen C. procarboxypeptidase A D. procarboxypeptidase B E. All of the answers are correct.  Clicker Question 2, Response Cholecystokinin stimulates the secretion of which pancreatic enzymes? E. All of the answers are correct. Arrival of peptides in the upper part of the intestine (duodenum) causes release into the blood of the hormone cholecystokinin, which stimulates secretion of several pancreatic proteases with activity optima at pH 7 to 8.  Clicker Question 3 The acidic and alkaline environments of the upper gastrointestinal tract promote what type of enzymes needed to activate pro-enzymes that are required for protein metabolism? A. aminotransferases B. mixed-function oxidases C. peptidases D. dehydrogenases E. hydratases  Clicker Question 3, Response The acidic and alkaline environments of the upper gastrointestinal tract promote what type of enzymes needed to activate pro-enzymes that are required for protein metabolism? C. peptidases Pepsinogen, an inactive pro-enzyme (zymogen) secreted in the stomach, is converted to active pepsin by an autocatalytic cleavage that occurs only at low pH. Pancreatic peptidases released into the small intestine have activity optima at pH 7 to 8.  The Intestinal Mucosa Absorbs Amino Acids free amino acids are transported into the epithelial cells lining the small intestine, enter the blood capillaries in the villi, and travel to the liver  Clicker Question 4 Dietary protein: A. is digested to small peptides that are then absorbed by intestinal cells. B. is digested completely to free amino acids, which then pass through intestinal cells into the lymph system. C. causes hormone-stimulated release of proteases from the stomach, pancreas, and intestine. D. is all completely digested.  Clicker Question 4, Response Dietary protein: C. causes hormone-stimulated release of proteases from the stomach, pancreas, and intestine. Entry of dietary protein into the stomach stimulates the gastric mucosa to secrete the hormone gastrin, which in turn stimulates the parietal cells and chief cells to secrete HCl and pepsinogen, respectively. Arrival of peptides in the upper part of the intestine (duodenum) causes release into the blood of the hormone cholecystokinin, which stimulates secretion of several pancreatic proteases.  Acute Pancreatitis acute pancreatitis = caused by obstruction of the pathway by which pancreatic secretions enter the intestine – zymogens are prematurely converted to their active forms inside the pancreatic cells and attack the pancreatic tissue  Principle 1 (2 of 7) The many paths for amino acid catabolism have two broad parts, one involving the amino groups and the other involving the carbon skeletons. All of the pathways for amino acid degradation include a key step, always involving a pyridoxal phosphate cofactor, in which the α-amino group is separated from the carbon skeleton and shunted into the pathways of amino group metabolism. The carbon skeletons are broken down to citric acid cycle intermediates.  Pyridoxal Phosphate Participates in the Transfer of α-Amino Groups to α-Ketoglutarate aminotransferases (transaminases) = catalyze the removal of the α-amino groups – cells contain different types that differ in their specificity for the L-amino acid – many are specific for α- ketoglutarate as the amino group acceptor  Principle 2 (3 of 4) Four amino acids—alanine, glutamate, glutamine, and aspartate—play key roles in the transport and distribution of amino groups. All are present in relatively high concentrations in one or many mammalian tissues. All are readily converted to key citric acid cycle intermediates.  Transamination Reactions transamination reactions = transfer the α-amino group to the α-carbon atom of α-ketoglutarate, yielding an α-keto acid analog of the amino acid – reactions are freely reversible (∆G′ ≈ 0 kJ/mol) – effectively collect the amino groups from many amino acids in the form of L-glutamate  Clicker Question 5 All enzyme-catalyzed aminotransferase reactions remove amino groups from amino acids, producing what byproduct that is important during metabolic stress? A. pyruvate B. a hydride and a H+ C. one of the ketone body molecules D. fumarate E. an α-keto acid  Clicker Question 5, Response All enzyme-catalyzed aminotransferase reactions remove amino groups from amino acids, producing what byproduct that is important during metabolic stress? E. an α-keto acid In reactions catalyzed by aminotransferases, the incoming amino acid binds to the active site, donates its amino group to pyridoxal phosphate (PLP), and departs in the form of an α-keto acid.  Principle 1 (3 of 7) The many paths for amino acid catabolism have two broad parts, one involving the amino groups and the other involving the carbon skeletons. All of the pathways for amino acid degradation include a key step, always involving a pyridoxal phosphate cofactor, in which the α-amino group is separated from the carbon skeleton and shunted into the pathways of amino group metabolism. The carbon skeletons are broken down to citric acid cycle intermediates.  Pyridoxal Phosphate (PLP) pyridoxal phosphate (PLP) = the coenzyme form of pyridoxine or vitamin B6 – used as a prosthetic group by all aminotransferases – carries amino groups at the active site  The Structure of Pyridoxal Phosphate and Pyridoxamine Phosphate PLP (aldehyde form) = accepts an amino group pyridoxamine phosphate (aminated form) = donates its amino group to an α-keto acid Pyridoxal Phosphate Is Covalently Linked to the Enzyme covalently linked through an aldimine (Schiff base) linkage to the ε-amino group of a Lys residue The Aldimine Linkage Is Replaced by the Amino Group the aldimine linkage is replaced by the amino group of the amino acid as the first step in most PLP-catalyzed reactions Some Reactions Facilitated by PLP transamination racemization decarboxylation  Clicker Question 6 Which statement about pyridoxal phosphate (PLP) is false? A. It is a coenzyme form of vitamin B6. B. All aminotransferases use it as a prosthetic group. C. It is only used by transaminases and by no other enzymes. D. It receives amino groups in transamination reactions.  Clicker Question 6, Response Which statement about pyridoxal phosphate (PLP) is false? C. It is only used by transaminases and by no other enzymes. We encountered PLP in Chapter 15, as a coenzyme in the glycogen phosphorylase reaction, but its role in that reaction is not representative of its usual coenzyme function. Its primary role in cells is in the metabolism of molecules with amino groups.  Principle 1 (4 of 7) The many paths for amino acid catabolism have two broad parts, one involving the amino groups and the other involving the carbon skeletons. All of the pathways for amino acid degradation include a key step, always involving a pyridoxal phosphate cofactor, in which the α-amino group is separated from the carbon skeleton and shunted into the pathways of amino group metabolism. The carbon skeletons are broken down to citric acid cycle intermediates. Glutamate Releases Its Amino Group as Ammonia in the Liver NH4+ in the mitochondria comes from many different α-amino acids in the form of: – the amino group of L-glutamate – the amide nitrogen of glutamine  Principle 3 (2 of 5) Metabolic pathways are not distinct. The various pathways for amino acid catabolism are elaborately intertwined with other catabolic and anabolic pathways.  L-Glutamate Dehydrogenase L-glutamate dehydrogenase = catalyzes the oxidative deamination of glutamate to produce NH4+ and α-ketoglutarate – present in the mitochondrial matrix – can use either NAD+ or NADP+ α-ketoglutarate can enter the citric acid cycle or be used for glucose synthesis  Transdeamination Reactions transdeamination reactions = result from the combined action of an aminotransferase and glutamate dehydrogenase  Clicker Question 7 Transdeamination involves: A. the α-amino groups from nearly all amino acids being transferred to glutamate by transaminations, followed by release of NH4+ from glutamate by L-glutamate dehydrogenase. B. release of α-amino groups from nearly all amino acids by L-amino acid dehydrogenases. C. release of α-amino groups from nearly all amino acids by L-amino acid deaminases. D. the combined actions of transaminase and glutamine synthetase.  Clicker Question 7, Response Transdeamination involves: A. The α-amino groups from nearly all amino acids being transferred to glutamate by transaminations, followed by release of NH4+ from glutamate by L-glutamate dehydrogenase. The combined action of an aminotransferase and glutamate dehydrogenase is referred to as transdeamination.  Principle 1 (5 of 7) The many paths for amino acid catabolism have two broad parts, one involving the amino groups and the other involving the carbon skeletons. All of the pathways for amino acid degradation include a key step, always involving a pyridoxal phosphate cofactor, in which the α-amino group is separated from the carbon skeleton and shunted into the pathways of amino group metabolism. The carbon skeletons are broken down to citric acid cycle intermediates.  Principle 2 (4 of 4) Four amino acids—alanine, glutamate, glutamine, and aspartate—play key roles in the transport and distribution of amino groups. All are present in relatively high concentrations in one or many mammalian tissues. All are readily converted to key citric acid cycle intermediates.  Principle 3 (3 of 5) Metabolic pathways are not distinct. The various pathways for amino acid catabolism are elaborately intertwined with other catabolic and anabolic pathways. Glutamate Dehydrogenase Operates at an Important Intersection in Carbon and Nitrogen Metabolism α-ketoglutarate product can be oxidized as fuel or serve as a glucose precursor in gluconeogenesis glutamate dehydrogenase is: – positively modulated by ADP (signals low glucose levels) – negatively modulated by GTP (signals high levels of α- ketoglutarate)  Clicker Question 8 Glutamate dehydrogenase: A. converts glutamate to glutamine. B. converts glutamine to glutamate. C. converts glutamate to aspartate. D. deaminates glutamate to α-ketoglutarate. E. transaminates α-ketoglutarate to glutamate.  Clicker Question 8, Response Glutamate dehydrogenase: D. deaminates glutamate to α-ketoglutarate. In hepatocytes, glutamate is transported from the cytosol into mitochondria. Here, it undergoes oxidative deamination catalyzed by L-glutamate dehydrogenase to produce NH4+ and α-ketoglutarate.  Principle 4 (3 of 3) Free ammonia is toxic. Excess amino groups must be safely excreted. In mammals, the urea cycle serves this purpose. Glutamine Transports Ammonia in the Bloodstream glutamine synthetase = catalyzes the combination of free ammonia with glutamate to yield glutamine – requires ATP – critical to transport toxic ammonia to the liver glutaminase = catalyzes the conversion of glutamine to glutamate and NH4+ Alanine Transports Ammonia from Skeletal Muscles to the Liver skeletal muscles produce pyruvate, lactate, and ammonia alanine aminotransferase = interconverts pyruvate and alanine via transamination with glutamate  The Glucose-Alanine Cycle glucose-alanine cycle = pathway by which alanine carries ammonia and the carbon skeleton from pyruvate to the liver – ammonia is excreted – pyruvate is used to produce glucose, which is returned to the muscle  Clicker Question 9 Amino acids are not stored in appreciable concentrations. However, which amino acid would be found in significant concentration in the blood of basketball players after a long and intense workout in a gym? A. histidine B. alanine C. glutamine D. cysteine E. proline  Clicker Question 9, Response Amino acids are not stored in appreciable concentrations. However, which amino acid would be found in significant concentration in the blood of basketball players after a long and intense workout in a gym? B. alanine In skeletal muscle, excess amino groups are generally transferred to pyruvate to form alanine, an important molecule in the transport of amino groups to the liver.  Clicker Question 10 What is the primary role of the glucose-alanine cycle? A. converting glucose to alanine B. delivering amino groups from the muscle to the liver C. delivering de novo synthesized glucose from the liver to the muscle D. enhancing protein degradation E. preventing glucose accumulation in the muscle  Clicker Question 10, Response What is the primary role of the glucose-alanine cycle? B. delivering amino groups from the muscle to the liver Alanine largely supplants glutamine in the transport of amino groups from muscle to the liver in a nontoxic form, ultimately delivering the free ammonia to hepatocyte mitochondria via glutamate in a pathway called the glucose-alanine cycle.  Ammonia Is Toxic to Animals free ammonia is toxic, especially to the brain NH4+ competes with K+ for transport into astrocyte cells through Na+K+ ATPase – results in elevated extracellular [K+] Na+-K+-2Cl- cotransporter 1 (NKCC1) = symporter that transports Na+, K+, and Cl- – excess Cl- from the excess K+ alters neuronal response to the neurotransmitter GABA 18.2 Nitrogen Excretion and the Urea Cycle  The Urea Cycle urea cycle = pathway by which the ammonia deposited in the mitochondria of hepatocytes is converted to urea – urea enters the bloodstream and is excreted into the urine – enzymes are clustered in metabolons  Clicker Question 11 The urea cycle itself requires two different cellular compartments. What other pathway also requires two cellular compartments? A. glycolysis B. pentose phosphate, oxidative phase C. β oxidation D. gluconeogenesis E. glyoxylate  Clicker Question 11, Response The urea cycle itself requires two different cellular compartments. What other pathway also requires two cellular compartments? D. gluconeogenesis The urea cycle and gluconeogenesis both have steps that take place in the cytosol as well as steps that take place in the mitochondria. Urea Is Produced from Ammonia in Five Enzymatic Steps carbamoyl phosphate synthetase I = catalyzes the formation of carbamoyl phosphate from NH4+ and CO2 (as HCO3-) – requires 2 ATP – occurs in the mitochondrial matrix  The Carbamoyl Phosphate Synthetase I Reaction the first nitrogen enters from ammonia in the reaction catalyzed by carbamoyl phosphate synthetase I the reaction has two activation steps that require ATP  The Formation of Citrulline ornithine transcarbamoylase = catalyzes the formation of citrulline and Pi from ornithine and carbamoyl phosphate  Clicker Question 12 The urea cycle: A. can be used to make uric acid by oxidation of urea in the liver. B. occurs primarily in the kidneys. C. can be used to generate NH4+ from urea. D. uses two unusual α-amino acids as intermediates.  Clicker Question 12, Response The urea cycle: D. uses two unusual α-amino acids as intermediates. The α-amino acids citrulline and ornithine are both intermediates of the urea cycle. The Formation of Argininosuccinate citrulline passes from the mitochondrion to the cytosol argininosuccinate synthetase = catalyzes the condensation of the amino group of aspartate and the ureido group of citrulline to form argininosuccinate – requires ATP – uses a citrullyl-AMP intermediate  The Argininosuccinate Synthetase Reaction the second nitrogen enters from ammonia in the reaction catalyzed by argininosuccinate synthetase the reaction has two activation steps  The Formation of Arginine argininosuccinase = catalyzes the reversible cleavage of argininosuccinate to form arginine and fumarate – fumarate is converted to malate and joins the pool of citric acid cycle intermediates  The Formation of Urea arginase = catalyzes the cleavage of arginine to form urea and ornithine – ornithine is transported into the mitochondrion to initiate another round  Clicker Question 13 Two nitrogen-containing groups are used to make urea in liver cells. Which two molecules of the urea cycle contribute to those two groups? A. carbamoyl phosphate and aspartate B. alanine and glutamate C. glutamate and glutamine D. carbamoyl phosphate and glutamate E. arginine and aspartate  Clicker Question 13, Response Two nitrogen-containing groups are used to make urea in liver cells. Which two molecules of the urea cycle contribute to those two groups? A. carbamoyl phosphate and aspartate Both carbamoyl phosphate and aspartate are reactants of the cycle, and both contribute one amino group. The Citric Acid and Urea Cycles Can Be Linked Communication Between the Citric Acid and Urea Cycles communication depends on the transport of key intermediates between the mitochondrion and cytosol: – malate–α-ketoglutarate transporter – glutamate-aspartate transporter – glutamate-OH- transporter The Aspartate-Argininosuccinate Shunt aspartate-argininosuccinate shunt = pathways linking the citric acid and urea cycles – link the fates of the amino groups and the carbon skeletons of amino groups  Clicker Question 14 Which molecule that is produced in the cytosol by the urea cycle can be used by the citric acid cycle but cannot pass the inner mitochondrial membrane? A. malate B. arginosuccinate C. ornithine D. NAD+ E. fumarate  Clicker Question 14, Response Which molecule that is produced in the cytosol by the urea cycle can be used by the citric acid cycle but cannot pass the inner mitochondrial membrane? E. fumarate The urea cycle results in a net conversion of oxaloacetate to fumarate, both of which are intermediates in the citric acid cycle. However, fumarate must be converted to malate before it can enter the mitochondrion.  Principle 3 (4 of 5) Metabolic pathways are not distinct. The various pathways for amino acid catabolism are elaborately intertwined with other catabolic and anabolic pathways.  Aspartate as a Nitrogen Donor this pathway for nitrogen incorporation is one of the two common ways to introduce amino groups into biomolecules the urea and citric acid cycles are closely tied to an additional process that brings NADH, in the form of reducing equivalents, into the mitochondrion  The Activity of the Urea Cycle Is Regulated at Two Levels the urea cycle is regulated: – at the level of enzyme synthesis for: the four urea cycle enzymes carbamoyl phosphate synthetase I – by allosteric regulation of carbamoyl phosphate synthetase I Synthesis of N-Acetylglutamate and Its Activation of Carbamoyl Phosphate Synthetase I N-acetylglutamate synthase = catalyzes the formation of N- acetylglutamate from acetyl-CoA and glutamate N-acetylglutamate = allosterically activates carbamoyl phosphate synthetase I  Clicker Question 15 How is the urea cycle regulated? A. A diet rich in carbohydrates and lipids results in downregulation of the five urea cycle enzymes. B. Arginine stimulates the urea cycle by activating N-acetylglutamate synthase. C. Starvation or ingestion of protein-rich diets upregulates urea cycle enzymes. D. Carbamoyl phosphate synthetase I is allosterically regulated by N-acetylglutamate. E. All of the answers are correct.  Clicker Question 15, Response How is the urea cycle regulated? E. All of the answers are correct. All five urea cycle enzymes are synthesized at higher rates in starving animals and in animals on very-high-protein diets than in well-fed animals eating primarily carbohydrates and fats. Carbamoyl phosphate synthetase I is allosterically activated by N‐acetylglutamate, and arginine is an activator of N‐acetylglutamate synthase.  Pathway Interconnections Reduce the Energetic Cost of Urea Synthesis in isolation, the urea cycle requires four high-energy phosphate groups 2NH4+ + HCO3- + 3ATP4- + H2O → urea + 2ADP3- + 4Pi2- + AMP2- + 2H+ the energetic cost of the urea cycle is reduced by cycle interconnections  Clicker Question 16 The bioenergetics of the urea cycle are: A. recovered when ATP is produced in the breakdown of urea in the kidneys. B. such that its energetic cost is compensated for by the Krebs bicycle and its associated reactions. C. such that the overall reaction of the cycle shows the energetic equivalent of the hydrolysis of 3 ATP to ADP and Pi. D. such that ATP is only hydrolyzed by carbamoyl phosphate synthetase I.  Clicker Question 16, Response The bioenergetics of the urea cycle are: B. such that its energetic cost is compensated for by the Krebs bicycle and its associated reactions. The fumarate generated by the urea cycle is converted to malate, and the malate is transported into the mitochondrion. Inside the mitochondrial matrix, NADH is generated in the malate dehydrogenase reaction. Each NADH molecule can generate up to 2.5 ATP during mitochondrial respiration, greatly reducing the overall energetic cost of urea synthesis. Genetic Defects in the Urea Cycle Can Be Life-Threatening protein-free diets are not a treatment option for individuals with defects in urea cycle enzyme essential amino acids = amino acids that cannot be synthesized by humans and must be obtained in the diet  Clicker Question 17 Which compound is an essential amino acid? A. glutamate B. alanine C. threonine D. serine E. aspartate  Clicker Question 17, Response Which compound is an essential amino acid? C. threonine Humans can synthesize glutamate, alanine, serine, and aspartate from other compounds. However, humans cannot synthesize threonine and must acquire it from the diet, making it an essential amino acid.  Treatments for Urea Cycle Enzyme Deficiencies the aromatic acid benzoate is metabolized and combines with glycine the aromatic acid phenylbutyrate is metabolized and combines with glutamine  Clicker Question 18 Which statement regarding genetic defects in the urea cycle is false? A. In some cases, supplementation of the diet with arginine can be helpful; in others, arginine must be eliminated from the diet. B. One of the major problems that can occur is hyperammonemia. C. Some affected patients manage their disease with a protein-free diet. D. A person with any defect in an enzyme of the cycle cannot tolerate a protein-rich diet.  Clicker Question 18, Response Which statement regarding genetic defects in the urea cycle is false? C. Some affected patients manage their disease with a protein-free diet. Although the breakdown of amino acids can have serious health consequences in individuals with urea cycle deficiencies, a protein-free diet is not a treatment option. 18.3 Pathways of Amino Acid Degradation  Amino Acid Catabolism accounts for 10-15% of human energy production the 20 catabolic pathways converge to form six major products (all of which enter the citric acid cycle): – pyruvate – acetyl-CoA – α-ketoglutarate – succinyl-CoA – fumarate – oxaloacetate Summary of Amino Acid Catabolism  Clicker Question 19 Which compound is NOT considered a degradation product of an amino acid? A. citrate B. acetyl-CoA C. pyruvate D. succinyl-CoA  Clicker Question 19, Response Which compound is NOT considered a degradation product of an amino acid? A. citrate None of the 20 proteinogenic amino acids degrades to citrate.  Principle 5 (2 of 6) Each amino acid has a different catabolic fate. The varied carbon skeletons of amino acids are broken down via equally varied pathways. All can be oxidized to generate ATP. All but leucine and lysine can contribute to gluconeogenesis when needed.  Some Amino Acids Can Contribute to Gluconeogenesis, Others to Ketone Body Formation ketogenic amino acids = can yield ketone bodies in the liver – phenylalanine, tyrosine, isoleucine, leucine, tryptophan, threonine, and lysine glucogenic amino acids = can be converted to glucose and glycogen – all amino acids except lysine and leucine  Clicker Question 20 Amino acids: A. are solely ketogenic in only three cases. B. that are ketogenic lead to ketone bodies that do not contribute to diabetic ketoacidosis. C. are either ketogenic or glucogenic, but never both. D. that are glucogenic all produce oxaloacetate and then glucose.  Clicker Question 20, Response Amino acids: D. that are glucogenic all produce oxaloacetate and then glucose. Although only two amino acids (aspartate and asparagine) are directly degraded to oxaloacetate, the other products of glucogenic amino acid degradation (pyruvate, α-ketoglutarate, succinyl-CoA, and fumarate) can be converted to oxaloacetate through the pathways described in Chapter 14. The oxaloacetate is then shunted into gluconeogenesis.  Clicker Question 21 What is the metabolic use of ketogenic amino acids? A. All are used to produce α-ketoglutarate for the citric acid cycle. B. All are used to produce ketone bodies. C. All are used to produce the keto forms of carbohydrates that substitute for glycolytic intermediates. D. All are used as one-carbon donors for the formation of α-keto acids. E. All are used in ketogenesis, the formation of ketone- containing amino acids.  Clicker Question 21, Response What is the metabolic use of ketogenic amino acids? B. All are used to produce ketone bodies. The seven ketogenic amino acids that are degraded entirely or in part to acetoacetyl-CoA and/or acetyl-CoA can yield ketone bodies in the liver, where acetoacetyl-CoA is converted to acetoacetate and then to acetone and β-hydroxybutyrate. Several Enzyme Cofactors Play Important Roles in Amino Acid Catabolism one-carbon transfers usually involve one of three cofactors: – biotin (transfers CO2) – tetrahydrofolate (transfers intermediate oxidation states) – S-adenosylmethionine (transfers methyl groups)  Clicker Question 22 Amino acid oxidation requires cofactors that can serve as a one-carbon source for amino acid and nucleotide synthesis. Which molecule does NOT function as a one-carbon transfer molecule? A. pyridoxal phosphate B. biotin C. S-adenosylmethionine D. tetrahydrofolate E. All of these are involved in one-carbon transfers.  Clicker Question 22, Response Amino acid oxidation requires cofactors that can serve as a one-carbon source for amino acid and nucleotide synthesis. Which molecule does NOT function as a one-carbon transfer molecule? A. pyridoxal phosphate Pyridoxal phosphate is the common cofactor for aminotransferases, whereas biotin, S-adenosylmethionine, and tetrahydrofolate function as one-carbon transfer molecules.  Tetrahydrofolate (H4 Folate) tetrahydrofolate (H4 folate) = consists of substituted pterin (6- methylpterin), p-aminobenzoate, and glutamate moieties – synthesized in bacteria folate = the oxidized form of tetrahydrofolate – converted to tetrahydrofolate in two steps by dihydrofolate reductase Conversions of One-Carbon Units on Tetrahydrofolate the one-carbon group is bonded to N-5, N-10, or both  Clicker Question 23 Tetrahydrofolate metabolism: A. allows for easy transfer of methyl groups from a folate derivative to the substrate in most biochemical methylations. B. results in folate derivatives carrying one-carbon units of varying oxidation states. C. involves one-carbon metabolism with the one-carbon units attached to the S-adenosyl moiety of folate derivatives. D. is not linked to vitamin B12.  Clicker Question 23, Response Tetrahydrofolate metabolism: B. results in folate derivatives carrying one-carbon units of varying oxidation states. The most reduced form of the tetrahydrofolate cofactor carries a methyl group, a more oxidized form carries a methylene group, and the most oxidized forms carry a methenyl, formyl, or formimino group. S-Adenosylmethionine (adoMet) S-adenosylmethionine (adoMet) = preferred cofactor for biological methyl group transfers – Its methyl group is ~ 1000x more reactive than the methyl group of N5-methyltetrahydrofolate methionine adenosyl transferase = catalyzes the synthesis of S-adenosylmethionine from ATP and methionine S-adenosylhomocysteine = formed when the methyl group from S-adenosylmethionine is transferred to an acceptor Synthesis of Methionine and S-Adenosylmethionine  Pernicious Anemia pernicious anemia = observed in B12 deficiency disease – traced to the methionine synthase reaction  Megaloblatic Anemia megaloblastic anemia = observed in vitamin B12 deficiency – decline in the production of mature erythrocytes – appearance of immature precursor cells, or megaloblasts, in the bone marrow – replacement of erythrocytes with a smaller number of abnormally large erythrocytes (macrocytes) erythocyte defects are due to the depletion of the N5,N10-methylenetetrahydrofolate  Clicker Question 24 Which statement is false about vitamin B12 deficiency? A. It leads to the formation of small erythrocytes. B. It causes both anemia and neurological symptoms. C. Metabolic folates become trapped in the N5-methyl form. D. The anemia symptoms can be alleviated by administering folate.  Clicker Question 24, Response Which statement is false about vitamin B12 deficiency? A. It leads to the formation of small erythrocytes. The anemia associated with vitamin B12 deficiency is called megaloblastic anemia. It manifests as a decline in the production of mature erythrocytes (red blood cells) and the appearance in the bone marrow of immature precursor cells, or megaloblasts. Erythrocytes are gradually replaced in the blood by smaller numbers of abnormally large erythrocytes called macrocytes.  Tetrahydrobiopterin tetrahydrobiopterin = cofactor of amino acid catabolism – similar to the pterin moiety of tetrahydrofolate – participates in oxidation reactions  Principle 1 (6 of 7) The many paths for amino acid catabolism have two broad parts, one involving the amino groups and the other involving the carbon skeletons. All of the pathways for amino acid degradation include a key step, always involving a pyridoxal phosphate cofactor, in which the α-amino group is separated from the carbon skeleton and shunted into the pathways of amino group metabolism. The carbon skeletons are broken down to citric acid cycle intermediates.  Principle 3 (5 of 5) Metabolic pathways are not distinct. The various pathways for amino acid catabolism are elaborately intertwined with other catabolic and anabolic pathways.  Principle 5 (3 of 6) Each amino acid has a different catabolic fate. The varied carbon skeletons of amino acids are broken down via equally varied pathways. All can be oxidized to generate ATP. All but leucine and lysine can contribute to gluconeogenesis when needed.  Six Amino Acids Are Degraded to Pyruvate alanine, tryptophan, cysteine, serine, glycine, and threonine are converted in whole or in part to pyruvate pyruvate is either converted to: – acetyl-CoA for oxidation via the citric acid cycle – oxaloacetate to enter gluconeogenesis Amino Acid Degradation to Pyruvate  Serine Dehydratase serine dehydratase = catalyzes the conversion of serine to pyruvate – removes both the β-hydroxyl and the α-amino groups of serine – pyridoxal phosphate–dependent reaction  Clicker Question 25 When serine is converted into pyruvate, what is the source of the carbonyl oxygen on pyruvate? A. serine B. water C. carbon dioxide D. glycine E. phosphate  Clicker Question 25, Response When serine is converted into pyruvate, what is the source of the carbonyl oxygen on pyruvate? B. water The final step of the serine dehydratase reaction is a hydrolytic deamination in which water displaces ammonia.  Glycine Degradation by Serine Hydroxymethyltransferase serine hydroxymethyltransferase = catalyzes the enzymatic addition of a hydroxymethyl group to glycine to yield serine – requires tetrahydrofolate and pyridoxal phosphate  Glycine Degradation by Glycine Cleavage Enzyme glycine cleavage enzyme = catalyzes the reversible oxidative cleavage of glycine to CO2, NH4+, and a methylene group – requires tetrahydrofolate – enzymatic defects causes the formation of methylglyoxal, which modifies proteins and DNA  Glycine Degradation by D-Amino Acid Oxidase D-amino acid oxidase = catalyzes the conversion of glycine to glyoxylate, which is oxidized to oxalate calcium oxalate crystals account for up to 75% of all kidney stones  Clicker Question 26 Which statement does NOT describe one of the pathways for glycine degradation? A. Glycine is converted to serine, which is converted to pyruvate. B. In an oxidative cleavage pathway, glycine loses one carbon as CO2 and the other becomes the methylene group of N5,N10-methylenetetrahydrofolate. C. Glycine is converted to acetyl-CoA, which enters the citric acid cycle. D. Glycine is converted to glyoxylate, which is oxidized to oxalate.  Clicker Question 26, Response Which statement does NOT describe one of the pathways for glycine degradation? C. Glycine is converted to acetyl-CoA, which enters the citric acid cycle. Glycine is an exclusively glucogenic amino acid, meaning it cannot be degraded entirely or in part to acetyl-CoA or acetoacetyl-CoA.  Genetic Defects of Amino Acid Metabolism Table 18-2 Some Human Genetic Disorders Affecting Amino Acid Catabolism Medical condition Approximate Defective process Defective enzyme Symptoms and effect incidence (per 100,000 births) Albinism